Process and system for predicting responders and non-responders to mesalamine treatment of ulcerative colitis

ABSTRACT

A process and system directed to a more effective, individual based treatment regimen which is built on clinical identified target biomarkers associated with gender differential responses to mesalamine, and includes one or more panels of target biomarkers that distinguishes mesalamine response differences between genders and determines the efficacy of mesalamine for patients being treated for various UC conditions and effectively identifies and validates novel drug targets for new UC therapeutics, new diagnostics and diagnostics standards for UC therapeutic strategies.

This application is a divisional application of and claims benefit inits entirety of U.S. patent application Ser. No. 15/068,981 filed Mar.14, 2016, titled: Process and System for Predicting Responders andNon-Responders to Mesalamine Treatment of Ulcerative Colitis.

BACKGROUND OF THE INVENTION

Ulcerative colitis (UC) is a form of inflammatory bowel disease (IBD)that appears in the large intestine or colon with periods of exacerbatedsymptoms and periods that are relatively symptom free. UC patients oftenexperience the same symptoms as irritable bowel syndrome (IBS) patients,which is a much less serious condition, making a definitive diagnosismuch more complicated. Similarly, patients with indeterminate colitismay have a form of colitis that is different from UC, and more similarto Crohn's colitis, another related form of intestinal IBD.

Symptoms of UC are anatomically heterogeneous in their presentationbetween patients. UC patients for example can present with disease in arange of extent from the recto-sigmoid only on to degrees of involvementincluding the entire colon. Initially, patients treated medically may bestarted on non-specific anti-inflammatory medications, most commonlymesalamine (5-ASA). Non-responders to a trial of medications may then beescalated in their therapy with cytotoxic or biologic medications. This“step-up” approach typically using mesalamine to treat active UC, isassociated with clinical treatment failures in 60% of patients withmoderate UC, compared to 80% treated with placebo. Moreover, a clinicalresponse favoring doses of mesalamine greater than 2.5 grams per day hasnot been clearly shown despite clinical practice to the contrary.

Since biologics are associated with significantly increased costscompared to oral anti-inflammatory drugs, the early identification ofpatients who do not respond to mesalamine or conversely, who wouldrespond to other therapies is important. The “step-up” medicationstrategy currently used does not take gender difference intoconsideration nor the locations of the disease within the colon. Thesame drug intervention strategy is applied to almost all UC patients,which is believed to be one of the key factors responsible for the highclinical treatment failure.

Numerous systems have been developed for inflammatory bowel disease(IBD) biomarkers including the use of fecal calprotectin and lactoferrinproteins for identifying patients with inflammatory bowel disease (IBD),assessing disease severity and for predicting relapses; the use of serumanti-Saccharomyces cerevisiae antibody (ASCA) and perinuclearantoneutriphil cytoplasmic antibody (pANCA) biomarkers to differentiateCrohn's Disease (CD) from UC; and the use of serum anti-OmpC IgAanti-CBir1 biomarkers with ASCA and other biomarker assays for IBDdiagnosis as well as UC and CD differentiation. IBD disease biomarkersincluding anti-GM-CSF antibody, CD11b, TNF-a, CRP, aldo-keto reductasefamily 1 B10 (AKR1B10), perforin, NF-kB, CXC-chemokines, aquaporins,kinesins, adaptor protein-1 (AP-1), C5a, IL-2R, integrins, HCC-4, IL-7,MCP-1, MSP protein, IL-11, G-CSF, adrenoreceptors, ST2, E-cadhein, KC,IL-12/23p40, IL-17, chlorotyrosine, PAP/REG3, MIF, DMBT1, LCN2, IL-22,haptoglobin, CCL20, IL-6, IL-33, CAP37, E4A (UBE4A), CXCL16, resistin,apolipoprotein A-IV, beta-defensin, NOD2/CARD15, NOD1/CARD4, toll-likereceptors (TLR) 2 and 4, leptin, adiponectin, IL-10, DPP-IV, and CXCR4have also been identified. Such biomarkers have been used fordetermining the responsiveness of steroid and biological treatments.However, until now, there have been no method or system developed fordetermining the responsiveness of a patient to mesalamine for thetreatment of active UC.

As previously stated, one of the first lines of conventional UC clinicaltreatment is the use of mesalamine (5-ASA). However, the efficacy ofmesalamine in active UC is only about 30-40%. UC pathophysiology andfactors that influence the response to mesalamine treatment are not wellknown. The identified significant differences in protein profiling fromdifferent genders and anatomic colitis locations demonstrate that UC isa complicated disease. Accordingly, a need exists for a process andsystem for predicting the potential efficacy of a patient's response tomesalamine suffering from UC. It is also desirable to have a process anda system for developing an effective strategy for treatment of patientssuffering from UC and a new, safe, effective, and potentially gender andcolitis location dependent therapeutics.

SUMMARY OF THE INVENTION

The process and system of the subject invention is directed to a moreeffective, individual based treatment regimen which is built usingclinical identified target biomarkers. In a preferred embodiment of theinvention, the biomarkers identified herein establishes a foundation ofUC target biomarkers associated with gender differential responses tomesalamine, and includes panels identifying protein target biomarkersthat distinguishes mesalamine response differences between genders.Accordingly, the subject invention is directed to a process and systemfor determining the efficacy of mesalamine for patients being treatedfor various UC conditions. The subject invention is also directed to aprocess and system for developing effective strategies for the treatmentof patients suffering from UC and to new, safe, effective, andpotentially gender and colitis location dependent therapeutics.

Preferred embodiments of the subject invention are a process and asystem that utilizes gender and disease locations to effectively developnew diagnostics and diagnostics standards for UC therapeutic strategies.

Another preferred embodiment of the subject invention utilizes genderand disease locations to permit personalized clinical UC medicationregimens based on an individual patient's biomarker profiles.

Another preferred embodiment of the subject invention operates toidentify mesalamine non-responders at a relatively early stage of UCusing one or more panels of target biomarkers which allows for thedevelopment of a clinical medication approach having greater mesalamineefficacy.

Another preferred embodiment of the subject invention operates toidentify mesalamine non-responders at a relatively early stage of UCusing one or more panels of target biomarkers which allow faster andeffective disease control with alternative treatments.

A preferred embodiment of the invention the panel is for male and femalepancolitis and extensive colitis and comprises one or more targetbiomarkers selected from a list consisting of GSTM1, IL13, RETN andHistone H2a autoantibody.

Another preferred embodiment of the invention the panel is for femaleleft sided colitis and comprises one or more target biomarkers selectedfrom a list consisting of antibody to L. donovani, antibody to HTCLV1/2,and HSP90alpha autoantibody.

Another preferred embodiment of the invention the panel is for male leftsided colitis and comprises one or more target biomarkers selected froma list consisting of APOA1, PRL, HSP 71 autoantibody and IgA.

Another preferred embodiment of the invention the panel is for femaleproctosigmoiditis and comprises one or more target biomarkers selectedfrom the list consisting of CCL22 and antibody to cholera toxin.

Another preferred embodiment of the invention the panel is for maleproctosigmoiditis and comprises one or more target biomarkers selectedfrom the list consisting of ILRN and CD40 LG.

A preferred embodiment of the invention, the identified targetbiomarkers are gender dependent biomarkers.

Another preferred embodiment of the invention the identified targetbiomarkers are effective for predicting efficacy of mesalamine patientswith pancolitis and extensive colitis.

Another preferred embodiment of the invention the identified targetbiomarkers are effective for predicting efficacy of mesalamine 2.4 g and4.8 g daily therapy, given for 6 weeks to female and male patients withpancolitis and extensive colitis, and are selected from a panelcomprising a list having one or more target biomarkers consisting ofModel 1: GSTM1, IL13 and Histone H2a autoantibody and Model 2: HistoneH2A autoantibody and REIN target biomarkers.

Another preferred embodiment of the invention the identified targetbiomarkers are effective for predicting the efficacy of mesalamine 2.4 gand 4.8 g daily therapy, given for 6 weeks for female patients withleft-sided colitis, and are selected from a panel comprising a list oneor more target biomarkers consisting of antibody to L. donovani,antibody to HTCLV 1/2, HSP90 alpha autoantibody target biomarkers.

Another preferred embodiment of the invention the identified targetbiomarkers are effective for predicting the efficacy of mesalamine 2.4 gand 4.8 g daily therapy, given for 6 weeks for male patients withleft-sided colitis, and are selected from the panel comprising a list ofone or more target biomarkers consisting of HSP 71 autoantibody, IgA,APOA1 and PRL target biomarkers.

Another preferred embodiment of the invention the identified targetbiomarkers are effective for predicting the efficacy of mesalamine 2.4 gand 4.8 g daily therapy, given for 6 weeks for female patients withproctosigmoiditis and are selected from the panel comprising a list ofone or more target biomarkers consisting of CCL22, and antibody tocholera toxin.

Another preferred embodiment of the invention the identified targetbiomarkers are effective for predicting the efficacy of mesalamine 2.4 gand 4.8 g daily therapy, given for 6 weeks for male patients withproctosigmoiditis, and are selected from a panel comprising a list ofone or more target biomarkers consisting of IL1RN, and CD40L.

A preferred embodiment of the invention is a process for predicting apatient's response to mesalamine for the treatment of ulcerative colitis(UC), the process comprises the steps of: identifying a patientdiagnosed with UC; determining the location of the ulcerative colitis;obtaining a blood sample from the patient; using the sample to form ablood component; selecting a panel having one or more target biomarkersfor the diagnosed UC, location and gender of the patient; using theblood component to make a determination as to the existence and quantityof one or more of the target biomarkers in the blood component; andusing the determination to create an outcome that predicts theeffectiveness of mesalamine treatment for the patient.

In a preferred embodiment of the invention the panel comprises levels ofone or more target biomarkers selected from the list consisting ofGSTM1, IL13, RETN and Histone H2a autoantibody effective for use increating outcomes for male and female patients having pancolitis andextensive colitis.

In a preferred embodiment of the invention the panel comprises levels ofone or more target biomarkers selected from the list consisting ofantibody to L. donovani, antibody to HTCLV 1/2 and HSP90alphaautoantibody effective for use in creating outcomes for female leftsided colitis.

In a preferred embodiment of the invention the panel comprises levels ofone or more target biomarkers selected from the list consisting ofAPOA1, PRL, HSP 71 autoantibody and IgA effective for use in creatingoutcomes for male left sided colitis.

In a preferred embodiment of the invention the panel comprises one ormore target biomarkers selected from the list consisting of CCL22 andantibody to cholera toxin effective for use in creating outcomes forfemale proctosigmoiditis.

In a preferred embodiment of the invention the panel comprises one ormore target biomarkers selected from the list consisting of ILRN andCD40 LG effective for use in creating outcomes for maleproctosigmoiditis.

In a preferred embodiment of the invention one or more panels areeffective for predicting efficacy of mesalamine patients with pancolitisand extensive colitis.

Another preferred embodiment of the invention is a process for definingspecific UC disease biomarkers as to gender and colitis locationscomprising the steps of: obtaining a sample from the patient; using thesample to form a blood component, such as a serum, identifying one ormore target biomarkers from the blood component and the levels of theidentified target biomarkers, and using the levels of the identifiedtarget biomarkers to create an outcome that diagnoses mild-to-moderateulcerative colitis disease.

In a preferred embodiment of the invention the process further comprisesthe step of using the panel and the levels and/or the change in levelsof the one or more target biomarkers to develop novel UC therapeutics asnew drug targets or as means to identify new drug targets or as means toscreen new drug therapeutics.

A preferred embodiment of the invention is a process for predicting apatient's response to mesalamine for the treatment of ulcerative colitis(UC), the process comprises the steps of identifying a patient diagnosedwith UC, determining the location of the UC, obtaining a first bloodsample from the patient, mixing the blood sample with one or moreseparators to create a first blood component, selecting a panel, whereinthe panel identifies one or more target biomarkers for the location ofthe UC and the gender of the patient, determining the level of each ofthe one or more target biomarkers in the first blood component, making afirst comparison of the levels of the one or more target biomarkers inthe first blood component to levels in a reference, and using the firstcomparison to create an outcome predicting the effectiveness ofmesalamine treatment for the patient.

A preferred embodiment of the invention is a process for the treatmentof ulcerative colitis (UC), the process comprises the steps ofidentifying a patient diagnosed with UC, determining the location of theUC, obtaining a first blood sample from the patient, creating a bloodcomponent devoid of red and white blood cells by mixing the first bloodsample with one or more separators, selecting a panel based on thelocation and gender of the UC wherein the panel identifies one or moretarget biomarkers, making a determination of the existence and level ofthe one or more of the identified target biomarkers in the first bloodcomponent, administering a treatment to the patient for the UC,obtaining a second blood sample from the patient and mixing the secondblood sample with one or more separators to create a second bloodcomponent, determining the level of each of the one or more targetbiomarkers in the second blood component, making a second comparison ofthe levels of the one of more target biomarkers in the second bloodcomponent to the levels of the one or more target biomarkers in thefirst blood component, and using the second comparison to evaluate theeffectiveness of the treatment.

In a preferred embodiment of the invention the process furthercomprising the steps of identifying one or more compounds or proteinsthat effect, produces, or modifies one or more of the identified targetbiomarkers, and creating a treatment for the UC disease wherein suchtreatment is based on one or more of the identified compounds orproteins.

In another preferred embodiment of the invention further comprising thesteps of identifying changes in one or more of the target biomarkerscaused by one or more compounds or proteins and using the identifiedchanges to analyze the disease mechanism of the type of UC beingevaluated.

A preferred embodiment of the invention is a process for predicting apatient's response to mesalamine for the treatment of ulcerative colitis(UC), the process comprises the steps of: identifying the location ofthe UC, obtaining a blood sample from the patient diagnosed with the UC,forming a blood component by mixing the blood sample with one or moreseparators, selecting a panel identifying one or more target biomarkersbased on the location and gender of the patient, using the bloodcomponent to make a determination as to the existence and quantity ofone or more of said target biomarkers in the blood component, and usingthe determination to create an outcome that predicts the effectivenessof mesalamine treatment for the patient.

In a preferred embodiment of the invention the one or more separatorsare selected from the list consisting of an EDTA coated tube, and/or aHeparin coated tube, and/or a Citrate coated tube.

In a preferred embodiment of the invention the one or more separatorsare anticoagulants.

Other embodiments, advantages and objects of the invention will beapparent from the following description and the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

To provide a more complete understanding of the present invention andfurther features and advantages thereof, reference is now made to thefollowing description taken in conjunction with the accompanyingdrawings, in which:

FIG. 1 is a schematic representation illustrating the system of thesubject invention whereby a blood component comprising a blood samplefrom a patient diagnosed with a form of UC is mixed with one or moreseparators to form a blood component that is devoid of red and whiteblood cells, a panel identifying one or more target biomarkers based ongender and location of the UC, the blood component further compriseslevels (quantity) of one or more target biomarkers, and a reference forcomparing the levels of the target biomarkers for creating an outcome;

FIG. 2 is a flow diagram showing the general methodology of the processfor predicting efficacy of mesalamine for patients being treated for adiagnosed UC condition;

FIG. 3 illustrates specific biomarker panels for a patient diagnosedwith UC based on the gender of the patient and the location of the UC;

FIGS. 4A and 4B shows Table 1 displaying significant univariate analyteswith a p value of less than 0.2 which were used to build the finalbiomarker multivariate model for success or failure of male/femalepan/extensive colitis and also shows distribution of proteins thatpredict success or failure of 5ASA within subgroups;

FIG. 5 shows Table 2 displaying descriptive ranges of location andgender specific biomarkers;

FIG. 6 shows Table 3 displaying predictive models for location andgender;

FIG. 7 shows Table 4 displaying significant univariate analytes with pvalues of less than 0.2 which were used to build the final biomarkermultivariate model for success or failure of female left-sided colitisUC patients;

FIG. 8A and FIG. 8B shows Table 5 displaying significant univariateanalytes with p vales of less than 0.2, which were used to build thefinal biomarker multivariate model for success or failure of maleleft-sided ulcerative colitis patients;

FIG. 9 shows Table 6 displaying significant univariate analytes with pvalue of less than 0.2, which are used to build the final biomarkermultivariate model for success or failure of proctosigmoiditis UC femalepatients;

FIG. 10 shows Table 7 displaying male proctosigmoiditis univariateanalytes used for multivariate modeling;

FIG. 11 shows Table 8 displaying a list of target biomarkers for malelocations of proctosigmoiditis, left-sided colitis andextensive/pancolitis that can be used for drug development, compoundscreening, diagnostics, and monitoring therapeutic responses;

FIG. 12 shows Table 9 displaying a list of target biomarkers for malelocations of proctosigmoiditis, left-sides and extensive/pancolitis thatcan be used for drug development, compound screening, diagnostics, andmonitoring therapeutic responses;

FIG. 13 shows Table 10 displaying the list of target biomarkers for maleproctosigmoiditis, left-sided and pan/extensive that can be used fordrug development, compound screening, diagnostics, and monitoringtherapeutic responses;

FIG. 14 shows Table 11 displaying a list of target biomarkers for femalelocations of proctosigmoiditis, left-sided and extensive/pancolitis thatcan be used for drug development, compound screening, diagnostics, andmonitoring therapeutic responses;

FIG. 15 shows Table 12 displaying a list of target biomarkers for femalelocations of proctosigmoiditis, left-sides and extensive/pancolits thatcan be used for drug development, compound screening, diagnostics, andmonitoring therapeutic responses;

FIG. 16 shows Table 13 displaying the list of target biomarkers forfemale proctosigmoiditis, left-sided and pan/extensive that can be usedfor drug development, compound screening, diagnostics, and monitoringtherapeutic responses;

FIG. 17 is a flow diagram of the general methodology of a preferredembodiment of the invention showing the process of creating an outcomethat predicts the efficiency of an administered medication; and

FIG. 18 is a flow diagram of the general methodology of a preferredembodiment of the invention showing the process used for drugdevelopment, compound screening, diagnostics and monitoring therapeuticresponses using the system of the subject invention.

DETAILED DESCRIPTION OF THE INVENTION

Using mesalamine to treat active UC is associated with clinicaltreatment failures in 60% of patients with moderate UC, compared to 80%of those treated with placebo. Due to the lack of understanding ofdisease pathophysiology, until now, mesalamine treatment did not takegender difference into consideration nor the locations of the diseasewithin the colon. Patients, such as those with left-sided colitis andproctosigmoiditis are difficult to manage clinically. However, patientswith proctosigmoiditis do not have greatly increased predilection todeveloping colon cancer. This is different from those patients withpancolitis and extensive colitis that have significantly higher risk ofdeveloping colon cancer. Therefore, it is desirable to have a processand system that are effective for use in specifically predictingmesalamine treatment responses for subgroups of patients having UC aswell as for use in developing effective strategies for the treatment ofpatients suffering from UC as well as for developing new and effectivetherapeutics effective for the treatment of UC at different anatomiccolon locations.

In a preferred embodiment, the subject invention comprises panels ofprotein biomarkers (“target biomarkers”) that distinguish mesalamineresponse differences between genders and anatomic colitis locations.Using these panels of target biomarkers as described herein, mesalaminenon-responders can be identified earlier. Further, using such panels oftarget biomarkers a new clinical medication process has been developedhaving greater efficacy and is faster and more effective for diseasecontrol while allowing for alternative treatments for thenon-responders.

Preferably, the process or system of the subject invention comprise twocategories of panels that identify target biomarkers based on theirdifferences in utility. The first category of panels provides a list ofidentify target biomarkers that are gender dependent and operate topredict mesalamine treatment outcomes (success or failure) formild-to-moderate UC patients. The method and system utilize the panelsas unique tools allowing physicians to decide optimal personalized UCtherapy strategies. The process and system further utilize differentpanels identifying target biomarkers for patients with colitis indifferent colonic locations.

The second category of panels provide a list of identified targetbiomarkers used for mild-to-moderate UC disease for specific genders atdifferent colitis locations. The panels operate for determining andvalidating new UC drug targets. The panels comprise listings ofidentified target biomarkers that are used for new drug targetsthemselves, or are used in understanding UC mechanism and to determineor identify other molecules, proteins, and the like for new therapeutictargets. The panels identifying disease target biomarkers are also usedas tools for screening UC therapeutic compounds, as well as fordiagnosing mild-to-moderate UC.

First Category: Gender Dependent Target Biomarkers for PredictingMesalamine Treatment Outcomes

In a preferred embodiment, the system and process of the subjectinvention utilize a first category of gender dependent target biomarkersto create outcomes that predict the efficacy of mesalamine treatment(success or failure) on mild-to-moderate UC patients with differentcolitis locations (left-sided colitis, proctosigmoiditis, pancolitis,and extensive colitis).

As illustrated in FIGS. 1 and 2, the system 100 and process of thesubject invention comprises identifying a patient P diagnosed with UC(step 200) and determining the location of the UC (step 202). A venousblood sample B is taken from the patient P (step 204) and a specifiedblood component 102, such as in the form of a serum or plasma, iscreated by mixing the blood sample B with one or more separators 106(step 206). As used herein, the term “serum,” unless otherwise stated,refers to both serum and plasma. In a preferred embodiment, the bloodcomponent 102 is in the form of a plasma (not a serum) and is created byplacing the blood sample B into at least one selected tube 104 coatedwith or having one or more separators 106, such as an EDTA coated tube,and/or a Heparin coated tube, and/or a Citrate coated tube to create thespecified blood component 102, such as an EDTA plasma, and/or a Heparinplasma, and/or a citrate plasma, respectively. Another preferredembodiment of the invention, the blood component 102 is in the form of aserum (not plasma) created and using a venous blood sample B drawn froma patient P into at least one selected tube 104 having one or moreseparators 106, such as physical serum separators (i.e. SST tubes).After the venous blood B is drawn into the selected tube 104 it isimmediately inverted 3-5 times, so that the various serum separators 106(anticoagulants), are mixed into the blood sample B creating the bloodcomponent 102 in the form of a serum (not plasma) devoid of red andwhite blood cells. Each of the one or more tubes 104 having the mixtureof blood sample B and separators 106 is rested for up to 30-60 minutesat room temperature and then centrifuged at either room temperature orat 4-8° C. for 20 minutes at 1800-2000 rpm. For a blood component 102 inthe form of a plasma, once the blood sample B is drawn into one or moreof the tubes 104, the tubes are inverted 3-5 times to mix the bloodsample with the separators 106 (EDTA and/or Heparin and/or Citrate) andcentrifuged at either room temperature or at 4-8° C. for 20 minutes at1800-2000 rpm. After centrifugation, the cells of the blood sample willpellet to the bottom of the tube or get separated physically by theseparator and a purified blood component in the form of a serum orplasma is collected.

Referring to FIG. 3, the subject invention further utilizes one or morepanels 108 identifying one or more target biomarkers 110. The one ormore panels 108 preferably comprises a first panel 112 is shown andidentifies gender dependent target biomarkers 110. Upon evaluation ofstatistical analysis data (p values, t values risk ratio, estimates andeffect increments), the target biomarkers 110 identified in the firstpanel 112 were selected as being effective for use in predictingefficacy of mesalamine (2.4 g and 4.8 g daily therapy, given for sixweeks) for female and male patients with pancolitis and extensivecolitis and can be are used individually or in any combination forpredicting mesalamine efficacy.

The one or more panels 108 preferably further comprises a second panel116 identifying gender dependent target biomarkers 110 as shown and uponevaluation of statistical analysis data (p values, t values, risk ratio,estimates and effect increments), were selected as being effective foruse in predicting efficacy of mesalamine (2.4 g and 4.8 g daily therapy,given for six weeks) for female patients with left-sided colitis and areused individually or in any combination for predicting mesalamineefficacy.

The one or more panels 108 preferably further comprises a third panel120 identifying gender dependent target biomarkers 110 as shown and uponevaluation of the statistical analysis data (p values, t values, riskratio, estimates and effect increments), were selected as beingeffective in predicting efficacy of mesalamine (2.4 g and 4.8 g dailytherapy, given for six weeks) for male patients with left-sided colitisand are used individually or in any combination for predictingmesalamine efficacy.

The one or more panels 108 preferably further comprises a fourth panel124 identifying gender dependent target biomarkers 110 as shown and uponevaluation of the statistical analysis data (p values, t values, riskratio, estimates and effect increments), were selected as beingeffective in predicting efficacy of mesalamine (2.4 g and 4.8 g dailytherapy, given for six weeks) for female patients with proctosigmoiditisand are used individually or in any combination for predictingmesalamine efficacy.

The one or more panels 108 preferably further comprises a fifth panel128 of gender dependent target biomarkers 110 as shown and uponevaluation of the statistical analysis data (p values, t values, riskratio, estimates and effect increments), were selected as beingeffective in predicting efficacy of mesalamine (2.4 g and 4.8 g dailytherapy, given for six weeks) for male patients with proctosigmoiditisand are used individually or in any combination to predict mesalamineefficacy.

It should be understood that one aspect of the subject inventionprovides a process and system whereby panels of gender dependent targetbiomarkers are used as for predicting mesalamine treatment outcomes onmild- to moderate UC patients with different colitis locations(left-sided colitis, proctosigmoiditis, pancolitis and extensivecolitis). Such outcome predictions can be made by comparing the levelsof such target biomarkers in patients with a reference to determine ifthe levels (quantity) of target biomarkers are higher or lower than thelevels disclosed in the reference. Such differences are then used tocreate outcomes predicting the effectiveness of mesalamine treatment forthe patient. Having now generally described the invention, the same willbe more readily understood through reference to the following exampleswhich are provided by way of illustration, are not intended to belimiting of the present invention, unless specified.

Exemplary Illustrations of Preferred Embodiments A. Use of MesalamineNon-Responder Serum (or Plasma) Biomarkers in Personalized UC ClinicalPractice

Using mesalamine to treat active UC is associated with clinicaltreatment fails in 60% of patients with moderate UC, compared to 80%treated with placebo. Due to the lack of understanding of diseasepathophysiology, until now conventional mesalamine treatments did nottake gender difference into consideration nor the locations of thedisease within the colon. The panels of the subject invention operate toidentify protein target biomarkers and use such target biomarkers tocreate outcomes with regard to mesalamine response for patients based onthe patient's gender and anatomic colitis locations. Accordingly, thepanels identifying specific target biomarkers operate to allow users toidentify mesalamine non-responders earlier. Further, using such panelsnew clinical medication approaches are administered that have greaterefficacy and alternative treatments for non-responders can beadministered at an earlier stage of the disease.

By way of a non-limiting example, the subject invention providesoutcomes that predict mesalamine responses on pancolitis and extensivecolitis UC patients. Referring to FIGS. 1 and 2, in a preferredembodiment of the invention the process includes the step of identifyinga patient that has been diagnosed as having UC (step 200). The coloniccolitis location is then determined (step 202) such as by colonoscopy aspart of standard clinic procedures. A clinician obtains one or moreblood samples B (step 204) and creates a blood component 102 (step 206),such as in the form of a serum, as described above, and using theappropriate panel 108 identifies non-responder target biomarkers 110 asdisclosed hereinabove (step 208), determines the levels (quantity) ofthe target biomarkers in the blood component 102 (step 210) prior totreatment of this patient's active colitis and compares the levels withlevels of a reference 128 (step 212). Table 1 (FIGS. 4A and 4B) showssignificant univariate analytes with a p value of less than 0.2 whichwere used to build the final biomarker multivariate model (reference)for success or failure of male/female pan/extensive colitis in Tables 2and 3 (FIGS. 5 and 6, respectively). Table 1 also shows distribution ofproteins that predict success or failure of 5ASA within subgroups. InTables 2 and 3 the mean, standard error and range reported are reportedin pg/ml, ng/ml, or the MFI ratio for each valid biomarker. N totalindicates the total number of subjects within a subgroup withobservations for each protein. MFI ratio unit indicates the ratio ofmedian fluorescence intensity (MFI) of target-specific, antigen-coupledmicrospheres to MFI generated by a negative control microsphere testedin each sample well. The levels of the target biomarkers are thencompared to prescribed levels of a reference 128 as shown in Tables 2and 3 (FIGS. 5 and 6, respectively), (step 212) and an outcome 134 isgenerated (step 214). In a preferred embodiment of the invention theoutcome predicts the efficacy of mesalamine (2.4 g and 4.8 g dailytherapy, given for six weeks for female and male patients withpancolitis and extensive colitis). For example, if the patient showssignificant difference in levels of the specified mesalaminenon-responder target biomarkers (for example, higher serum level of IL13at baseline with a 1 pg/ml increase) then the outcome 134 will show thatit is likely that the patient will not respond to the mesalaminetreatment. It should be understood that Table 2 (FIG. 5) identifiesstatistically predictive serological biomarkers consisting of serumproteins, autoimmune antibodies and antibodies recognizing infectiousagents are shown for models of success vs. failure of 5ASA in each ofthe 5 subgroups. Effect increment indicates the quantitative incrementof each protein in pg/ml, ng/ml, MFI ratio unit, or 5ASA dosageassociated with the regression estimate and risk ratio. MFI ratio unitindicates the ratio of median fluorescence intensity (MFI) oftarget-specific, antigen-coupled microspheres to MFI generated by anegative control microsphere tested in each sample well. The values arestated in ng or pg/ml of protein as detected by the Rules-based medicineplatform. It should also be understood that Table 1 (FIGS. 4A and 4B)shows significant univariate RBM analytes with a p value of less than0.2 used for predictive multivariate modeling in male/femalePancolitis/Extensive.

In a preferred embodiment, in addition to the above mentioned panels oftarget biomarkers that are generic to both male and female pancolitisand extensive colitis patients, additional comparisons may be made usingpanels of additional target biomarkers, such as comparing levels offemale specific target biomarker (CCL22, antibodies to Cholera toxin, L.donovani, HTCLV1/2 and autoantibody to HSP90 alpha) or levels of malespecific target biomarkers may be used (IL1RN, CD40L, APOA1, PRL, IgAand autoantibody to HSP 71) as non-responder markers to determine if itis likely that this patient will not respond to mesalamine treatment.Consideration of an alternative drug therapy (such as anti-TNFmolecules) is then made (step 216).

In another preferred embodiment of the invention as shown in Table 4(FIG. 7), the subject invention provides a method and system for theprediction of mesalamine response on left-sided colitis UC femalepatients. Table 4 also shows significant univariate RBM analytes with pvalues of less than 0.2 used for multivariate and predictive modelingfemale left-sided colitis. In another non-limiting the method includesidentifying a patient that has been diagnosed with left-sided colitisUC. Left-sided colitis is verified such as by colonoscopy as part ofstandard clinic procedures. It should be understood that for left-sidedcolitis, mesalamine is the common medication prescribed to theindividual under current standard practice. Using the appropriatemesalamine non-responder target biomarkers identified hereinabove, aclinician runs one or more blood tests and obtains samples and creates aserum and identifies and determines the levels of one or more targetbiomarkers prior to treatment of the patient's active colitis. Thelevels of the target biomarkers are then be compared to levels or areference, such as shown in Tables 2 and 3 (FIGS. 5 and 6,respectively), and an output is generated that predicts the efficacy ofmesalamine (2.4 g and 4.8 g daily therapy, given for six weeks for maleand female patients with left-sided colitis UC) is made. For example, ifthe patient shows significant difference in levels of the specifiedmesalamine non-responder target markers (for example MFI or proteinlevel changes for antibody to L. donovani, Antibody to HTCLV1/2,HSP90alpha autoantibody for female patients with left-sided colitis,then a prediction is made that it is likely that the patient will orwill not respond to the mesalamine treatment depending on the proteindirectionality outlined in Tables 2 and 3. Consideration of another drugtherapy (such as anti-TNF molecules) could also be made at that time.

In another preferred embodiment of the invention, the subject inventionincludes a process and system for predicting mesalamine response onleft-sided colitis UC male patients. Table 5 (FIG. 8) shows significantunivariate analytes with p vales of less than 0.2, which were used tobuild the final biomarker multivariate model (reference) for success orfailure of left-sided colitis UC male patients in Tables 2 and 3 (FIGS.5 and 6, respectively). The process includes identifying a patienthaving UC, such as diagnosed with left-sided colitis UC. The conditionand location are verified such as by colonoscopy as part of standardclinic procedures. It should be understood that for left-sided colitis,mesalamine is the common medication prescribed to the individual undercurrent standard practice. Using the appropriate panel identifyingmesalamine non-responder target biomarkers described hereinabove, aclinician runs one or more blood tests and obtains a blood sample usingand creates a blood component, such as plasma or serum. The levels ofthe target biomarkers are determined prior to treatment of thispatient's active colitis. The levels of the target biomarkers arecompared to levels of a reference, such as shown in Tables 2 and 3(FIGS. 5 and 6, respectively) and an outcome that predicts the efficacyof mesalamine, such as 2.4 g or 4.8 g daily therapy, given for six weeksfor male and female patients with left-sided colitis UC, is made. Forexample, if the patient shows significant difference in levels of thespecified mesalamine non-responder target markers (for example, MFI orprotein level changes for antibody to L. donovani, Antibody to HTCLV1/2,HSP90alpha autoantibody for female patients and to HSP 71 autoantibody,IgA, APOA1 and PRL for male patients with left-sided colitis, then anoutcome that predicts the likelihood that the patient will or will notrespond to the mesalamine treatment is made depending on the proteindirectionality outlined in Tables 2 and 3. In a preferred embodiment theoutcome further recommends an alternative drug therapy or regimen.

In another non-limiting example of the invention, the process and systemoperate to predict mesalamine response on proctosigmoiditis UC femalepatients is shown in Table 6 (FIG. 9). Table 6 also shows significantunivariate analytes with p value of less than 0.2, which were used tobuild the final biomarker multivariate model (reference) for success orfailure of proctosigmoiditis UC female patients in Tables 2 and 3 (FIGS.5 and 6). The process includes identifying a patient that has beendiagnosed with proctosigmoiditis UC. The proctosigmoiditis is verifiedsuch as by colonoscopy as part of standard clinic procedures. It shouldbe understood that for proctosigmoiditis, mesalamine is the commonmedication prescribed to the individual in current standard practice.Using the appropriate mesalamine non-responder target biomarkersidentified hereinabove, a clinician runs one or more blood tests andobtains a blood sample and creates a blood component, such as serum orplasma, and selects the proper panel and determines the levels of thetarget biomarkers prior to treatment of this patient's activeproctosigmoiditis. The levels of the target biomarkers are then comparedto levels of a reference, such as shown in Tables 2 and 3, and anoutcome is generated that predicts the efficacy of mesalamine (such asfor 2.4 g and 4.8 g daily therapy, given for six weeks for female andmale patients with proctosigmoiditis). For example, if the patient showssignificant difference in levels of the specified mesalaminenon-responder target biomarkers (i.e. CCL22 and antibody to choleratoxin for females) then it is likely that the patient will not respondto the mesalamine treatment. In a preferred embodiment, the outcomeincludes an alternate drug therapy or regimen. Table 6 (FIG. 9) showssignificant univariate analytes with a p value of less than 0.2, whichwere used to build the final biomarker multivariate model for success orfailure of female proctosigmoiditis in Tables 2 and 3.

In another non-limiting example of the invention, as shown in Table 7(FIG. 10), the subject invention is a process and system for predictingmesalamine response on male proctosigmoiditis UC patients. Table 7 alsoshows significant univariate analytes with p values of less than 0.2,which were used to build the final biomarker multivariate model(reference) for success or failure of proctosigmoiditis UC male patientsin Table 2 and 3 (FIGS. 5 and 6, respectively). The process includesidentifying a patient that has been diagnosed with proctosigmoiditis UC.The proctosigmoiditis is verified such as by colonoscopy as part ofstandard clinic procedures. It should be understood that forproctosigmoiditis, mesalamine is the common medication prescribed to theindividual under current standard practice. Using the appropriate panelidentifying mesalamine non-responder target biomarkers as describedhereinabove, a clinician runs one or more blood tests and obtains ablood sample and creates a blood component, such as serum or plasma, anddetermines the levels of the target biomarkers prior to treatment ofthis patient's active proctosigmoiditis. The levels of the targetbiomarkers are then be compared to levels of a reference, such as shownin Tables 2 and 3 (FIGS. 5 and 6, respectively) and an outcome isgenerated that that predicts the efficacy of mesalamine (2.4 g and 4.8 gdaily therapy, given for six weeks for male patients withproctosigmoiditis). For example, if the patient shows significantdifference in levels of the specified mesalamine non-responder targetbiomarkers (for example, IL1RN, CD40L for males, then it is likely thatthe patient will or will not respond to the mesalamine treatmentdepending on the directionality of the protein test as listed in Table 3(FIG. 6). Preferably, the outcome further includes an alternate drugtherapy.

B. Use of Serum Target Biomarkers for Diagnosis and New Drug Developmentof Mild-to-Moderate UC Disease

It should be understood that the target biomarkers identified in thepanels are gender and colitis location specific UC disease targetbiomarkers. In another preferred embodiment of the invention, the panelsare used for the early diagnosis of disease, localization of disease,the development of new personalized UC drugs, the measurement of theresponse to a drug treatment regimen or for assays for compoundscreening of therapeutics.

The following example illustrates the list of target biomarkers as shownin Tables 8-10 (FIGS. 11-13) for the male gender and Tables 11-13 (FIGS.14-16) for the female gender that can be used for drug development,compound screening, diagnostics, location of disease and monitoringtherapeutic responses. It should be understood to one skilled in the artthat since pancolitis and extensive colitis at these colonic locationshave a significantly greater risk of developing colon cancer thanpatients with disease limited to proctosigmotidis or left sided colitis,early diagnosis of the disease as well as effective therapeutics ishighly desirable. The target biomarkers identified herein in Tables 8-10(FIGS. 11-13) and Tables 11-13 (FIGS. 14-16) are gender and colitislocation specific UC disease biomarkers that can be applied as targetsof the early diagnosis of disease, for the development of newpersonalized UC drugs, further verification of disease locationdiagnosis, for the measurement of the response to drug therapy, or forassays for compound screening therapeutics.

In another preferred embodiment of the invention as shown in FIG. 17 thesubject invention uses target biomarkers for patients with a particularUC condition. The subject invention provides a process whereby (such asin a non-limiting illustrative example, where the patient is diagnosedwith pancolitis and extensive colitis) target biomarkers verify diseaselocation and are used for drug targets, medication screening,diagnostics, and for monitoring therapeutic responses. In thisparticular example, the process includes identifying the gender of thepatient that has been diagnosed with UC (step 300) and verifying thelocation of the UC such as by colonoscopy as part of standard clinicprocedures (step 302). A clinician runs one or more blood tests andobtains a first blood sample (step 304) and creates a first bloodcomponent, such as a serum, by mixing the first blood sample with one ormore separators (step 306). The appropriate panel for the patient'sgender and UC is selected that identifies one or more target biomarkers(step 308) and the levels of the target biomarkers prior to treatment ofthis patient's UC, such as active left-sided colitis, is determined(step 310). Medication is then given to the patient (step 312). Aclinician runs additional blood tests and obtains a second bloodsample(s) (step 314) and creates a second blood component (step 316),such as a serum. The levels of the target biomarkers in the second bloodcomponent are then compared to levels of target biomarkers of areference (step 318), such as for the particular colitis. In a preferredembodiment, as shown in FIG. 17, the reference comprises levels of thetarget biomarkers found in the first blood component.

In another non-limiting example, the reference comprises the levels ofthe target biomarkers shown in Tables 2 (FIG. 5) and 10 (FIG. 13) formale subject colitis and Tables 2 (FIG. 5) and 13 (FIG. 16) for femalesubject colitis. Depending on the changes in the levels of the targetbiomarkers (changes from levels found in the first blood component tolevels found in the second blood component), an outcome is created (step316) that predicts the efficacy of the administered medication. Forexample, if the patient shows significant difference in levels of thetarget biomarkers it can be determined that the proscribed medication isimproving the patient's condition or is not effective for improving thepatient's condition. It should now be apparent to one skilled in the artthat the subject invention allows for the development of newpersonalized UC drugs, for the measurement and monitoring of a patient'sresponse to drug therapy, or for assays for compound screeningtherapeutics.

In another non-limiting example the process includes identifying a maleor female patient that has been diagnosed with left-sided colitis. Theleft-sided colitis is verified such as by colonoscopy as part ofstandard clinic procedures. A clinician runs one or more blood tests andobtains a first blood sample and creates a first blood component, suchas a serum, and determines the levels of target biomarkers prior totreatment of this patient's active left-sided colitis. Medication isthen given to the patient. A clinician runs additional blood tests andobtains an additional blood sample and creates a second blood component,such as a serum. The levels of the target biomarkers are then comparedto levels of a reference, such as for an example as shown in Tables 2(FIG. 5) and 10 (FIG. 13) for a male and Tables 2 (FIG. 5) and 13 (FIG.16) for a female with pancolitis and extensive colitis and depending onthe changes in the levels of the target biomarkers, an outcome can becreated that predicts the efficacy of the administered medication. Forexample, if the patient shows significant difference in levels of thetarget biomarkers it can be determined that the proscribed medication isimproving the patient's condition or not.

The following non-limiting example illustrates a list of targetbiomarkers for left-sided colitis, as shown in Table 8 (FIG. 11) for amale and shown in Table 11 (FIG. 14) for a female, that can be used fordrug development, compound screening, diagnostics, and monitoringtherapeutic responses. In a preferred embodiment the process includesidentifying a patient that has been diagnosed with a particular UC, inthis example left-sided colitis. The left-sided colitis is verified suchas by colonoscopy as part of standard clinic procedures. A clinicianruns one or more blood tests and obtains a blood sample and creates ablood component, such as a serum, and determines the levels of targetbiomarkers prior to treatment of this patient's active left-sidedcolitis. Medication is then given to the patient. A clinician obtains asecond blood sample and creates a second blood component, such as aserum. The levels of the target biomarkers in the first blood componentare then compared to levels of target biomarkers in the second bloodcomponent (reference), and depending on the changes in the levels of thetarget biomarkers, an outcome can be created that predicts as to theefficacy of the administered medication is made. For example, if thepatient shows significant difference in levels of the target biomarkersit can be determined that the proscribed medication is improving thepatient's condition or not.

The following non-limiting example illustrates the list of targetbiomarkers for proctosigmoiditis, such as shown in Table 9 (FIG. 12) fora male and Table 12 (FIG. 15) for females, that can be used for drugdevelopment, compound screening, diagnostics, and monitoring therapeuticresponses. In a preferred embodiment the process includes identifying aparticular UC condition. In this illustrative example the patient hasbeen diagnosed with proctosigmoiditis. The proctosigmoiditis is verifiedsuch as by colonoscopy as part of standard clinic procedures. Aclinician runs one or more blood tests and obtains a first blood sampleand creates a blood component, such as a serum, and determines thelevels of target biomarkers prior to treatment of this patient's activeproctosigmoiditis. Medication is then given to the patient. A clinicianruns additional blood tests and obtains a second blood sample andcreates a blood component, such as a serum. The levels of the targetbiomarkers in the first blood component are then compared to levels ofthe second blood component (reference), and depending on the changes inthe levels of the target biomarkers, an outcome can be created thatpredicts the efficacy of the administered medication. For example, ifthe patient shows significant difference in levels of the targetbiomarkers it can be determined that the prescribed medication isimproving the patient's condition or not.

It should now be apparent to one skilled in the art that the presentinvention provides a process and system whereby panels of targetbiomarkers are used for risk assessment and predict with a high degreeof reliability the treatment outcome with respect to a patientexpressing higher than normal levels of targeted biomarkers and thusprovides substantive value in various aspects of patient caremanagement. It should also now be apparent to one skilled in the artthat the process and system of the subject invention prevents or reducesthe likelihood of treatment using ineffective medications as well asreducing the possibility of the patient experiencing un-necessary sideeffects of mesalamine as well as the potential delay in clinicalrecovery due to use of ineffective drug choice. Further, it should beunderstood that the process and system reduce a delay in in clinicalrecovery that could be clinically significant since pancolitis patientshave great risk in developing colon cancer. Accordingly, the use of theprocess and system (of personalized medicine for patients with UC) ofthe subject invention is very beneficial to the patient, the prescribingpractitioner, and insurance companies.

It should now be understood that the panels of target biomarkersidentified for the specific UC conditions and in conjunction with otherclinical factors, is used to tailor treatments for individual patientsincluding selecting specific drug treatments and administration regimes,as well used for developing treatments, therapies and medications. In apreferred embodiment, as shown in FIG. 18, the system and process of thesubject invention further comprises the steps of identifying in-vitro(cell based) and/or in vivo (animal) models for UC study (step 400). Itshould be understood that as used herein models can be individual(patient) or animal subjects for use in the study. For a particulargender and UC, the appropriate panel identifying one or more targetbiomarkers is selected (step 402). One or more compounds and/or proteinsthat effect, produces, or modifies the one or more target biomarkers areidentified (step 404) using standard procedures. Utilizing the changesin the one or more target biomarkers caused by the one or more compoundsand/or proteins, disease mechanisms of the UC are analyzed (step 406).It should now be apparent to one skilled in the art that the changes tothe identified target biomarkers caused by various compounds and/orproteins permits the creation of new, safe, effective and gender andlocation-based therapeutics to be developed (step 408). For example, ina non-limiting illustration medications can be conventionally developedthat modifies levels of target biomarkers in a blood component createdfrom a blood sample from a model suffering from UC until such levelsfall within a range of prescribed levels of target biomarkers. Inanother non-limiting illustration, after medication has beenadministered to the model and given time to react, the levels of thetarget biomarkers in a blood component created after treatment arecompared to levels of the target biomarkers in a blood component createdprior to treatment and the effectiveness of the new drug therapy isdetermined. For example, if the treatment alters one or more of thetarget biomarkers the efficacy of the administered medication can bedetermined and if the treatment is not effective, changes can be made tothe therapy. If the model shows significant difference in levels of thetarget biomarkers it can be determined that the proscribed medication isimproving the model's condition or is not effective in improving themodel's condition. Using the process and system of the subject inventioneffective dosage of the medication can also be conventionallydetermined.

Accordingly, the process and system of the subject invention is directedto a more effective, individual (personalized-medicine) based treatmentregimen which is built on panels of clinical identified biomarkers. Itshould now be apparent that the process and system of the subjectinvention provides an accurate and easy to administer process that canbe used for the diagnosis, prognosis, and therapy alternatives for thetreatment of UC. In a preferred embodiment of the invention the processof system of the subject invention provides means whereby panelsidentifying target biomarkers operate as drug targets that areconventionally used to develop new medications and therapies effectivefor the treatment of UC patients. For example, if a patient showssignificant difference in levels of the target biomarkers it can bedetermined that the proscribed medication is improving or not improvingthe patient's condition.

In another preferred embodiment of the invention the process and systemuse panels of target biomarkers as a screening mechanism toconventionally identify therapeutic compounds that may have atherapeutic benefit and potential use for medications to treat UCpatients. For example, by examining target biomarkers for a particularUC condition, compounds and/or proteins can be identified that are knownto effect, produce, modify, or change one or more of the targetbiomarkers. Such compounds and/or proteins can then be used to createmedications for that particular UC condition.

In another preferred embodiment of the invention, the process and systemuse panels of target biomarkers such that by comparing changes in thelevel of one or more of the target markers, as described above,therapeutic effectiveness of medications can be administered to UCpatients.

In another preferred embodiment of the invention the process and systemof the subject invention operates to identify additional proteins, bothupstream and downstream, of the disease pathway for a particular UCcondition. Such proteins are then used as additional target biomarkersfor creating medications for the particular UC condition. Further, aftersuch proteins are identified changes therein (and their effect on targetbiomarkers) are determined, such information is used to provide insightinto the disease mechanism of the particular UC condition.

In another preferred embodiment of the invention, the process and systemof subject invention uses panels of target biomarkers to monitor thetherapeutic efficacy of the medication being administered to a UCpatient.

Although the foregoing invention has been described in some detail forpurposes of clarity of understandings, it will be apparent that certainchanges and modifications may be practiced within the scope of theappended claims. It should now be apparent that the various embodimentspresented can be easily modified while keeping within the scope andspirit of the subject invention. Accordingly, it should be understoodthat the present disclosure is to be considered as exemplary of theprincipals of the invention and is not intended to limit the inventionto the embodiments and the specific examples illustrated and theinvention is not to be limited to the details given herein, but may bemodified within the scope and equivalents of the descriptions andexamples contained herein.

1. A process for the treatment of ulcerative colitis (UC), the processcomprises the steps of: identifying a patient diagnosed with UC;determining the gender of the patient; determining the location of theUC; obtaining a first blood sample from the patient; selecting one ormore target biomarkers based on the location and the gender of thepatient; determining the level of the selected one or more targetbiomarkers in the first blood sample; administering a treatment to thepatient based on the location and the gender of the patient; take asecond blood sample from the patient and determine the level of theselected one or more target biomarkers in the second blood sample;compare the level of the one or more target biomarkers in the secondblood sample to the level of the one or more target biomarkers in thefirst blood sample; continue administering the treatment to the patientor modify the treatment based on the comparison of the level of the oneor more target biomarkers in the second blood sample to the level of theone or more target biomarkers in the first blood sample.
 2. The processof claim 1 wherein the one or more target biomarkers for a male orfemale patient having pancolitis and extensive colitis are GSTM1, IL13,RETN and Histone H2a autoantibody; wherein the one or more targetbiomarkers for a female having left sided colitis are antibody to L.donovani, HTCLV1/2 and HSP90alpha autoantibody; wherein the one or moretarget biomarkers for a male patient having left sided colitis areAPOA1, PRL, HSP 71 autoantibody and IgA; wherein the one or more targetbiomarkers for a female patient having proctosigmoiditis are CCL22 andantibody to cholera toxin; and wherein the one or more target biomarkersfor a male patient having proctosigmoiditis are ILRN and CD40 LG.
 3. Aprocess for the treatment of ulcerative colitis (UC), the processcomprises the steps of: identifying a patient diagnosed with UC;identifying the gender sex of the patient; determining the location ofthe UC; obtaining a first blood sample from the patient; selecting apanel of target biomarkers based on the location of the UC and thegender of the patient; making a determination of the existence and levelof the one or more of the identified target biomarkers in the firstblood sample; administering a treatment to the patient for the UC basedon the determination of the existence and level of the one or more ofthe identified target biomarkers in the first blood sample; afteradministering the treatment to the patient, obtaining a second bloodsample from the patient; A determining the level of each of the one ormore target biomarkers in the second blood sample; making a secondcomparison of the levels of the one of more target biomarkers in thesecond blood sample the levels of the one or more target biomarkers inthe first blood sample; and using the second comparison to evaluate theeffectiveness of the treatment; wherein the panel for a male or femalepatient having pancolitis and extensive colitis, the identified targetbiomarkers are GSTM1, IL13, RETN and Histone H2a autoantibody; whereinthe panel for a female having left sided colitis, the identified targetbiomarkers are antibody to L. donovani, HTCLV1/2 and HSP90alphaautoantibody; wherein the panel for a male patient having left sidedcolitis, the identified target biomarkers are APOA1, PRL, HSP 71autoantibody and IgA; wherein the panel for a female patient havingproctosigmoiditis, the identified target biomarkers are CCL22 andantibody to cholera toxin; and wherein the panel for a male patienthaving proctosigmoiditis, the identified target biomarkers are ILRN andCD40 LG.
 4. The process of claim 3 wherein the first and second bloodsamples are mixed with one or more separators to devoid the first andsecond blood samples of red and white blood cells.
 5. The process ofclaim 4 wherein the one or more separators are anticoagulants.
 6. Aprocess of claim 3 further comprising the steps of: identifying one ormore compounds or proteins that effect, produces, or modifies one ormore of the identified target biomarkers; and wherein the treatment isbased on one or more of the identified compounds or proteins.
 7. Theprocess of claim 6 further comprising the steps of identifying changesin one or more of the target biomarkers caused by one or more compoundsor proteins and using the identified changes to analyze the diseasemechanism of the UC.